Structure and function in the uracil-DNA glycosylase superfamily

• Published in: Mutation research Vol. 460; no. 3-4; pp. 165 - 181
• Main Author: Pearl, Laurence H
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 30.08.2000
• Subjects: Amino Acid Sequence; Archaeal Proteins - chemistry; Bacterial Proteins - chemistry; Base Pairing; Cytosine - analogs & derivatives; Cytosine - metabolism; Deamination; DNA - chemistry; DNA - metabolism; DNA Damage; DNA Glycosylases; DNA Repair; Escherichia coli - enzymology; Escherichia coli Proteins; Herpesvirus 1, Human - enzymology; Models, Molecular; Molecular Sequence Data; Multigene Family; N-Glycosyl Hydrolases - chemistry; N-Glycosyl Hydrolases - classification; N-Glycosyl Hydrolases - genetics; N-Glycosyl Hydrolases - physiology; Point Mutation; Protein Binding; Protein Conformation; Sequence Alignment; Sequence Homology, Amino Acid; SMUG; Structure-Activity Relationship; Substrate Specificity; Thermotoga maritima - enzymology; Thymine DNA Glycosylase; Transition mutations; uracil; Uracil - chemistry; Uracil-DNA Glycosidase; Uracil-DNA glycosylase; Viral Proteins - chemistry; Transition mutations; Uracil-DNA glycosylase; SMUG
• ISSN: 0921-8777; 0027-5107; 1386-1476
• DOI: 10.1016/S0921-8777(00)00025-2

Deamination of cytosine to uracil is one of the major pro-mutagenic events in DNA, causing G:C→A:T transition mutations if not repaired before replication. Repair of uracil-DNA is achieved in a base-excision pathway initiated by a uracil-DNA glycosylase (UDG) enzyme of which four families have so far been identified. Family-1 enzymes are active against uracil in ssDNA and dsDNA, and recognise uracil explicitly in an extrahelical conformation via a combination of protein and bound-water interactions. Extrahelical recognition requires an efficient process of substrate location by ‘base-sampling’ probably by hopping or gliding along the DNA. Family-2 enzymes are mismatch specific and explicitly recognise the widowed guanine on the complementary strand rather than the extrahelical scissile pyrimidine. This allows a broader specificity so that some Family-2 enzymes can excise uracil and 3,N4-ethenocytosine from mismatches with guanine. Although structures are not yet available for Family-3 (SMUG) and Family-4 enzymes, sequence analysis suggests similar overall folds, and identifies common active site motifs but with a surprising lack of conservation of catalytic residues between members of the super-family.